Safety of pimecrolimus in
infants
The favorable safety profile of pimecrolimus in infants has been
demonstrated in the above described vehicle-controlled trials
(Table 1 ) (30, 46-48, 50, 51). Four of these trials were also
evaluated in a previously pooled safety analysis (66). In this safety
analysis, a total of 495 pimecrolimus-treated infants were compared with
a total of 193 infants who were treated with vehicle (66). Although
results of this analysis may have been confounded by larger patient
numbers in the pimecrolimus treatment group, rates of adverse events
(AEs) were similar between pimecrolimus and vehicle, except for teething
which was more commonly observed in pimecrolimus-treated infants (66).
All other AEs were disorders typically encountered during childhood,
such as nasopharyngitis, pyrexia, upper respiratory tract infections,
and bronchitis (66). Burning and erythema were the most frequently
reported application site reactions, occurring in less than 1% of
infants treated with pimecrolimus (66). Consistent with the low systemic
exposure of pimecrolimus in infants (Table 2 ), the pooled
safety analysis confirmed that use of pimecrolimus is not associated
with immunosuppression (66). Accordingly, the incidence of non-skin
infections was comparable between pimecrolimus and vehicle treatment
groups (relative risk: 1.015; 95% confidence interval [CI]
0.88-1.18). The incidence rates of bacterial, fungal, parasitic, and
viral skin infections were also not altered by pimecrolimus treatment
(66). To further evaluate the impact of topical pimecrolimus on the
developing immune system, seropositivity rates upon vaccination were
assessed in 91 infants, who had applied pimecrolimus for a median number
of 377.5 days during 2 years of follow-up (67). Results demonstrated
that topical application of pimecrolimus in infants did not interfere
with tetanus, diphtheria, measles, and rubella vaccination response
(67).
Despite numerous studies demonstrating that pimecrolimus was
well-tolerated in infants without evidence of immunosuppression, initial
safety and tolerability concerns remained due to the lack of long-term
safety data. Additional safety data were requested mainly to determine
the impact of pimecrolimus on the developing immune system, and to
counteract the link between pimecrolimus use and (skin) malignancies.
Since the implementation of the black-box warning, the 5-year PETITE
study, several epidemiological studies, post-marketing surveillance, and
the ongoing Pediatric Eczema Elective Registry (PEER), all aimed to
resolve these safety concerns (58, 68-73). The PETITE study reassured
that long-term use of topical pimecrolimus in infants was not related to
an increased incidence of 18 AEs, which were of primary clinical
interest because of safety signals reported in previous trials (58).
Over the 5-year study period, there were no differences in growth rates
between both treatments and not more than 1% of patients discontinued
their treatment. Similarly to the results from the vehicle-controlled
trials, use of pimecrolimus did not affect vaccination response of the
infants. Tetanus, hepatitis B, measles, varicella, and Hemophilus
influenzae type B antibody titers post vaccination were all considered
normal and comparable between infants who had used pimecrolimus or TCS
for the past 5 years. The PETITE study provided additional evidence that
use of pimecrolimus has no impact on the developing immune system by
demonstrating similar humoral and cellular immune responses with
pimecrolimus and TCS (58). Furthermore, ex vivo studies showed
that levels of CD3+ T-cells over time were comparable not only between
pimecrolimus and TCS, but also with historical controls. No malignancies
were observed in the pimecrolimus treatment group, and there were no
cases of cutaneous T-cell lymphoma or any other skin malignancy in any
of the almost 2,500 enrolled infants, out of which more than 1,000 had
used pimecrolimus on the long-term (58).
Additionally, five epidemiological studies were conducted to evaluate
the potential malignancy risk that is associated with the use of TCIs in
general, including pimecrolimus (Table 3 ) (68-70, 72, 74).
However, when interpreting results from these studies one should
consider that patients with AD are generally more prone to develop
cancer compared to patients without AD. This was demonstrated by a study
performed in the United Kingdom (UK), comparing more than 60,000
patients with AD across all ages with more than 4 million individuals
without AD. After adjusting for age and sex, patients with AD had an
increased risk to develop cancer in general (75). Specifically, AD was
found to be associated with increased incidences of lymphoma, melanoma,
and nonmelanoma skin cancer (NMSC) (75). Even when keeping this in mind,
none of the five epidemiological studies, involving more than 6.5
million patients with AD, showed an increased risk of lymphoma,
including T-cell cutaneous lymphoma, in patients with AD who had been
treated with pimecrolimus (Table 3 ). Consistent with these
results, a meta-analysis published by Legendre et al. (2015) failed to
find a correlation between pimecrolimus and risk of lymphoma when used
for the treatment of AD (Figure 1 ) (76).The same was true for
tacrolimus and low-potency TCS, whereas high-potency TCS were associated
with a small but significant increase in lymphoma risk (Figure
1 ) (76). However, there was a high level of heterogeneity between the
included studies and the results for high-potency TCS may have been
biased by disease severity, as high-potency TCS are mainly used for the
treatment of severe cases, which in itself is a risk factor for lymphoma
(68). Similarly, there was no association between topical use of
pimecrolimus and the incidence of NMSC based on a questionnaire that was
sent out to 5,000 adult patients with AD out of which 1,000 had NMSC
(77). Interestingly, the latter case-control study reported less cases
of NMSC in patients treated with TCIs, especially with pimecrolimus
(77). Because epidemiological data are retrospectively collected and
studies generally had a limited follow-up time, the PEER was initiated
in 2004 to prospectively gather post-marketing data in children with AD
between the ages of 2-17 years (71). To be included in the registry,
children had to be treated for at least 6 weeks with pimecrolimus prior
to enrolment into the registry. The primary aim of this nationwide,
observational registry in the US and Canada was to evaluate the possible
link between topical use of pimecrolimus and malignancy over a follow-up
period of 10 years (71). At the time of the first interim results, 7,457
children with AD were enrolled in the PEER for more than 25,000
person-year of follow-up. Over the 10-year study period, five
malignancies had been reported (2 leukemia, 1 osteosarcoma, and 2
lymphomas) (71). These malignancies were not considered drug-related and
the standardized incidence ratio for all malignancies as compared with
the Surveillance, Epidemiology and End Results (SEER) data was 1.2 (95%
CI 0.5-2.8), indicating that children exposed to pimecrolimus for the
treatment of AD are not at risk to develop cancer (71). As of March
2020, only five additional cases of malignancies were reported in the
PEER, evaluating data derived from 8,015 patients and including 45,960
person-year of follow-up (Meda data on file). Importantly, neither the
interim results nor the latest follow-up data, reported any cases of
skin cancer. Taken together, there is currently no clinical reason to
expect malignancies when using topical pimecrolimus for the treatment of
AD.